Machine learning-enabled design of prototype pathogen vaccines and antibodies

PROJECT SUMMARY - OVERALL: MACHINE LEARNING-ENABLED DESIGN OF PROTOTYPE PATHOGEN VACCINES AND ANTIBODIES We propose a highly synergistic Center focused on developing end-to-end strategies for pandemic preparedness vaccine development for bunyaviruses and paramyxoviruses. Our Center brings together five research institutions with complementary and synergistic expertise in computational protein design, structure-based vaccine design, mRNA vaccines, structural biology, viral entry, viral diversity and evolution, animal model development, high biosafety-level containment virology, vaccinology, and vaccine process development and technology transfer. Our team has real-world experience in vaccine and biologics product development in both academic and industry settings. Our Center comprises five Scientific Projects supported by three Scientific Cores, an Administrative Core, and a Data Management Core. Our Scientific Projects include: 1) Development of computational methods for vaccine and biologics design, 2) Fundamental research on viral entry and receptors, 3) Antigen design, 4) Protein nanoparticle vaccine development, and 5) mRNA vaccine development. We will structure our efforts in two phases: in Phase 1 (Years 1-3) we will focus on developing vaccines for our prototype pathogens and in Phase 2 (Years 4-5) we will apply those learnings to two new bunyaviruses and two new paramyxoviruses to demonstrate that our computational and experimental approaches generalize across viral families. Our prototype pathogens are: Lassa virus (LASV; arenaviruses), Rift Valley fever virus (RVFV; phenuiviruses), and Hendra virus (HeV; paramyxoviruses). We carefully selected our prototypes as we believe they present specific vaccine design challenges which, if we are successful in solving, will facilitate the development of vaccines against related viruses. Simultaneously, the antigens from viruses in these three families have some similarities that will give rise to synergies in our design approaches. The structure of our Center will allow maximal synergy between our groups in pursuit of its central output: to define generalizable approaches and tools to develop vaccines and biologics for emerging pathogens with pandemic potential.